Hematopoietic Stem Cell Transplant Population Research Articles

Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation

PurposeThere is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug.MethodsThe study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m2. A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in Monolix® software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO.ResultsPharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m2 in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m2 and 14 g/m2 in a 2 h infusion.ConclusionsA two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC0→∞.

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OBJECTIVES/SPECIFIC AIMS: Aim 1: To compare microbiome diversity among patients who develop BSI post hematopoietic stem cell transplantation (HSCT) and patients without BSI. Aim 2: To compare microbiome diversity among patients who develop moderate to severe acute GVHD post HSCT and patients without GVHD. Aim 3: To describe alterations in specific bacterial orders (Enterobacteriaceae, Clostridia, and Lactobacillales) in pediatric patients undergoing HSCT. METHODS/STUDY POPULATION: Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from stool specimens collected at baseline (start of preparative regimen to transplant day), early (day 7–14 post HSCT), and late (day 21–28 post HSCT) from 46 children was performed. Microbiome diversity was assessed by the Shannon index as well as UniFrac analysis, and compared among patients with and without GVHD/BSI. Baseline bacterial diversity was compared among patients by primary diagnosis, race, timing of antibiotic introduction and method of supplemental nutrition. RESULTS/ANTICIPATED RESULTS: Median age was 9 years (range 0.5–19.2 years). There were 36 patients with hematologic malignancies. Patients with nonmalignant disease had a characteristic pattern of microbiome diversity (and microbiota order distribution) at baseline that persisted throughout the first month of transplant (p=0.004). Over all patients, there was an early and persistent drop in microbiome diversity throughout the transplant course. Early introduction of broad spectrum antibiotics (prior to transplant day) negatively impacted microbiome diversity (p=0.02). There was no difference in microbiome diversity among patients who developed BSI, when compared with patients without BSI. Similarly, we did not find an association between microbiome diversity and the development of moderate to severe acute GVHD. Ongoing analysis is examining the individual variations in microbiome at the species level, and their relation to transplant characteristics and clinical outcomes. DISCUSSION/SIGNIFICANCE OF IMPACT: In our analysis, microbiome diversity decreased during HSCT, but in contrast to published data, mainly in adult HSCT populations, we found no association between gut microbiome diversity and GVHD or BSI. There are ongoing clinical trials in children and adults using probiotics in HSCT with the aim of decreasing GVHD. Further analysis of our data at the species level may further inform the relationship between gut microbiome alterations and HSCT complications in children and guide clinical interventions.

A pilot randomized trial of adjuvanted influenza vaccine in adult allogeneic hematopoietic stem cell transplant recipients

The annual influenza vaccine is recommended for hematopoietic stem cell transplant (HSCT) patients although studies have shown suboptimal immunogenicity. Influenza vaccine containing an oil-in-water emulsion adjuvant (MF59) may lead to greater immunogenicity in HSCT recipients. We randomized adult allogeneic HSCT patients to receive the 2015-2016 influenza vaccine with or without MF59 adjuvant. Preimmunization and 4-week post-immunization sera underwent strain-specific hemagglutination inhibition assay. We randomized 73 patients and 67 (35 adjuvanted; 32 non-adjuvanted) had paired samples available at follow-up. Median age was 54 years (range 22-74) and time from transplant was 380 days (range 85-8107). Concurrent graft-versus-host disease was seen in 42/73 (57.5%). Geometric mean titers increased significantly after vaccination in both groups. Seroconversion to at least one of three influenza antigens was present in 62.9% vs 53.1% in adjuvanted vs non-adjuvanted vaccine (P=0.42). Factors associated with lower seroconversion rates were use of calcineurin inhibitors (P<0.001) and shorter duration from transplantation (P=0.001). Seroconversion rates were greater in patients who got previous year influenza vaccination (82.6% vs 45.5%, P=0.03). Adjuvanted vaccine demonstrated similar immunogenicity to non-adjuvanted vaccine in the HSCT population and may be an option for some patients.

517 - Implementation of Xenon Ultraviolet-C Disinfection Robot to Reduce Hospital Acquired Infections in Hematopoietic Stem Cell Transplant Population

517 - Implementation of Xenon Ultraviolet-C Disinfection Robot to Reduce Hospital Acquired Infections in Hematopoietic Stem Cell Transplant Population

Respiratory Viral Detection in the Pediatric Hematopoietic Stem Cell Transplant Population

Respiratory viral infections (RVI) are a frequent cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. We examined clinical characteristics and respiratory viral detection in asymptomatic pediatric HSCT pre-transplant patients and symptomatic post-transplant patients. Coxsackie/echovirus (most common virus detected pre and post-transplant), rhinovirus, and coronavirus were detected pre-transplant and at the first post-transplant event suggesting persistent detection. None of the clinical characteristics examined were associated with viral detection and there was no increase in mortality noted with asymptomatic viral detection.

Yearly Long-Acting Zoledronic Acid (Reclast) Is Safe and Effective for Treatment of Bone Loss after Hematopoietic Stem Cell Transplantation

Background:With growing numbers of hematopoietic stem cell transplantation (HSCT) survivors due to more widespread use and better long-term outcomes, recognition and treatment of long-term complications of HSCT is important. Bone demineralization with resultant osteopenia and osteoporosis is one such common long-term complication with reported incidence of up to 50% of allogeneic HSCT survivors. Known risk factors include large cumulative doses of glucocorticoids, total body irradiation, calcineurin inhibitors and graft versus host disease, placing them at higher risk of developing bone demineralization compared to the general population. Zoledronic acid (ZA) is a long acting bisphosphonate which has not been well studied in the HSCT population for the treatment of bone loss. We hypothesize that the use of ZA in the post-HSCT setting is safe and effective in preserving bone density.Methods:We performed a retrospective IRB approved study evaluating patients after allogeneic HSCT at Vanderbilt University Medical Center (VUMC) from January 1, 2000 to December 31, 2015 who had evidence of bone demineralization and were treated with ZA. The patients who survived more than a year and who had surveillance dual-energy X-ray absorptiometry (DXA) scans following HSCT were selected for analysis. ZA (Reclast, 5 mg intravenous, Norvatis Pharmaceuticals Corp., Basel, Switzerland) was administered once yearly when the BMD from the DXA scan showed evidence of osteopenia (T-score -1 to -2.5) or osteoporosis (T-score < -2.5). BMD measurements, Z-scores, and T-scores were obtained for the lumbar spine and femur neck within 1 year after transplant and then every 2 to 3 years thereafter for surveillance. Stabilization was determined to be minimal change in the bone mineral density pre and post ZA ± 0.010.Results:A total of 564 patients were analyzed with 132 patients receiving ZA in the designated time frame. Of those patients, 56 patients had received surveillance DXA monitoring pre and post administration of ZA. Patients received between one to six doses of ZA with median three doses. In this patient population, 27 (48.2%) patients had improvement in BMD over the course of surveillance. 22 (39.3%) patients had stabilization in BMD and only 7 (12.5%) had had progressive bone loss despite being on ZA at a median of two years after starting ZA. All patients with progressive bone loss have been on two or more immunosuppressive therapy regimens including daily steroids for chronic GVHD. The average BMD of the lumbar spine prior to ZA was 1.036 ± 0.119 (Z-score -1.11 ± 1.07, T-score -1.46 ± 0.89) and after was 1.094 ± 0.114 (Z-score -0.46 ± 1.14; p = 0.01, T-score -0.94 ± 0.91; p = 0.02). The average BMD of the femur prior to ZA was 0.795 ± 0.106 (Z-score -1.10 ± 0.97, T-score -1.93 ± 0.89) and after was 0.791 ± 0.116 (Z-score -0.5 ± 1.11; p = 0.06, T-score -0.97 ± 0.90; p = 0.05). This shows that there was on average an improvement of BMD in the lumbar spine and stabilization of the femur hip BMD. ZA was generally well tolerated with one (0.8%) patient developing dyspepsia, one (0.8%) developing jaw pain without evidence of osteonecrosis of the jaw, and one (0.8%) patient developing bone pain after ZA administration. No patients developed renal dysfunction or osteonecrosis of the jaw as a result of ZA. Two patients did develop asymptomatic compression fractures while on treatment with ZA that were monitored and did not require surgical management.Conclusions:Yearly administration of a single dose of ZA is a safe and convenient intervention for the treatment of bone loss after HSCT. The majority of patients experienced either improvement or stabilization of their bone loss after receiving ZA. Prospective large-scale studies are needed to evaluate the efficacy of ZA for the prevention and treatment of bone loss in the HSCT population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Acute Leukemias: A Subgroup Analysis from the Defibrotide Expanded-Access Program

IntroductionHepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Reported mean incidence of VOD/SOS following HSCT is an estimated 13.7% (range 0%-62.3%). VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Endothelial cell (EC) damage, triggered by cytotoxic chemotherapeutic conditioning regimens and a prothrombotic-hypofibrinolytic state, is a critical factor in the pathophysiology of VOD/SOS. In the United States, defibrotide is approved for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT, and in the European Union, defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT. Prior to its approval, defibrotide had been available in the United States through an expanded-access program. Here, Day +100 post-HSCT survival and safety are analyzed for the 2 largest primary-disease subgroups in that study: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).MethodsPatients in the expanded-access program had VOD/SOS diagnosed by Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy, and this study included patients with or without MOD (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days.ResultsA total of 867 patients were enrolled in the safety population of the expanded-access program through April 18, 2015, including 476 patients with MOD. The primary diseases affecting 5% or more of the safety population at baseline were AML, 25.7% (222/867); ALL, 23.4% (202/867); neuroblastoma, 8.5% (73/867); and myelodysplastic syndrome, 5.7% (27/867).Data were available for 756 post-HSCT patients who received ≥1 dose of defibrotide. Of those patients, 207 (27.4%) patients had AML and 152 (20.1%) patients had ALL as their primary disease. Of the AML patients, 49.8% (103/207) were male, and 50.2% (104/207) were female; median age at HSCT was 23 years (range: 0.5, 74.0 years); and all had allogeneic HSCT. Among the ALL patients, 62.5% (95/152) were male, and 37.5% (57/152) were female; median age at HSCT was 16 years (range: 0.3, 68.0 years); and all had allogeneic HSCT.At Day +100 post-HSCT, observed survival was 45.4% (94/207) among AML patients and 42.8% (65/152) among ALL patients; 50.7% (105/207) and 52.0% (79/152), respectively, had died; and status was not available (ie, no HSCT date recorded, did not have sufficient follow-up, or their data were not available) for 3.9% (8/207) and 5.3% (8/152), respectively. For AML patients, Kaplan-Meier estimated survival rate was 47.8% (95% confidence interval [CI], 40.7%-54.5%; Figure 1); among ALL patients, Kaplan-Meier estimated survival rate was 46.0% (95% CI, 37.7%-53.9%; Figure 2).Adverse events (AEs) occurred in 76.8% (159/207) of AML patients and 64.5% (98/152) of ALL patients, with serious AEs in 57.5% (119/207) and 52.6% (80/152), respectively. Treatment-related AEs, as assessed by investigators, occurred in 21.7% (45/207) of AML patients and 17.1% (26/152) of ALL patients (>2% in either group [all <4%]: pulmonary hemorrhage, epistaxis, gastrointestinal hemorrhage, hypotension). Treatment-related AEs leading to discontinuation developed in 14.5% (30/207) of AML patients and 8.6% (13/152) of ALL patients (>2% in either group [all <3%]: pulmonary hemorrhage, gastrointestinal hemorrhage); treatment-related deaths occurred in 3.4% (7/207) of AML patients and 2.6% (4/152) of ALL patients, respectively, with none occurring in >1 patient in either subgroup.ConclusionsThe Day +100 survival rates and safety profile for the AML and ALL subgroups in the expanded-access program were consistent with prior defibrotide studies and analyses of the overall HSCT population in this study. Kaplan-Meier estimates of survival at Day +100 were similar between the AML (47.8%) and ALL (46.0%) subgroups. Taken together, these subgroup results affirm the overall efficacy and safety profile of defibrotide in post-HSCT patients with VOD/SOS and underlying acute leukemia.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresRichardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:The National Cancer Institute of the National Institutes of Health: Research Funding; Gentium: Research Funding. Grupp:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

Impact on Outcomes of Baseline Bilirubin in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Receiving Defibrotide Treatment: A Post-Hoc Analysis

IntroductionHepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a difficult to predict, and potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). VOD/SOS develops via a pathophysiologic cascade, and VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with >80% mortality. Defibrotide was recently approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and is approved in the European Union to treat severe hepatic VOD/SOS post-HSCT. In the United States, defibrotide had been available through an expanded-access program.MethodsPatients in the expanded-access program were diagnosed with VOD/SOS by investigators using Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of the following: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of the following: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy; elevated bilirubin was not required for patients with biopsy or who met modified Seattle criteria by presence of hepatomegaly with ascites/weight gain. This program included patients with or without MOD/MOF (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT is explored post hoc based on 4 bilirubin-level categories at time of study entry; together these categories have been defined as 1 of the criteria in the proposed VOD/SOS grading scale for adults from the European Society for Blood and Marrow Transplantation (EBMT; ≥2 mg/dL to <3 mg/dL, ≥3 mg/dL to <5 mg/dL, ≥5 mg/dL to <8 mg/dL, and ≥8 mg/dL [Mohty M et al. Bone Marrow Transplant. 2016;51:906-912]). It is important to note that bilirubin <2 mg/dL is not part of the proposed EBMT criteria for VOD/SOS in adults.ResultsAmong 756 post-HSCT patients enrolled through April 18, 2015, who received ≥1 dose of defibrotide, 427 also had MOD/MOF. Median age was lowest in patients with bilirubin <2 mg/dL (5 years). By comparison, median age in patients with bilirubin ≥2 to <3 mg/dL (56% of all patients) was 16 years; for bilirubin ≥3 to <5 mg/dL, median age was 13 years; and for the 2 small groups with bilirubin ≥5 to <8 or ≥8 mg/dL, median ages were 15 and 16.5 years, respectively.Day +100 survival in the overall HSCT population of the expanded-access program was 55.4% by Kaplan-Meier estimate. The survival rate was 81.4% in patients with bilirubin <2 mg/dL; for patients with bilirubin levels ≥2 mg/dL, who tended to be older, survival estimates decreased (Table). Day +100 survival patterns by bilirubin level were generally similar in the subgroups of patients with and without MOD/MOF (Table).Overall, 515 post-HSCT patients (67%) reported ≥1 adverse event (AE). Serious AEs were reported by 386 patients (50%), and AEs leading to death occurred in 250 patients (33%). Among all AEs, 158 patients (21%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication.ConclusionsOverall, higher bilirubin levels were associated with worse Day +100 outcomes (with the exception of the ≥5 to <8 mg/dL group, which represented only 5% of patients, and so has limited validity). However, interpretation of these results has to be treated with caution because only a single criterion from the EBMT guidelines was analyzed and because potentially confounding interactions (eg, age) were not assessed. Across all bilirubin-level categories, VOD/SOS with MOD/MOF was consistently associated with worse outcomes than VOD/SOS without MOD/MOF. These results further support the importance of identifying VOD/SOS earlier and suggest that diagnosis and treatment of VOD/SOS, before bilirubin becomes markedly elevated, may be associated with improved outcomes.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresRichardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Cytomegalovirus Retinitis in Pediatric Stem Cell Transplants: Report of a Recent Cluster and the Development of a Screening Protocol

The incidence of cytomegalovirus (CMV) retinitis in the pediatric allogeneic hematopoietic stem cell transplant (HSCT) population is unknown. We report a cluster of 5 pediatric patients with CMV retinitis diagnosed in a 12-month period and compare this to the rate of CMV viremia and retinitis in the 4 years prior. Presented is the ophthalmic screening protocol developed in response to this experience. Retrospective cross-sectional study. A retrospective chart review was performed on patients at Children's Hospital of Colorado (CHCO) who received allogeneic HSCT between January 2010 and December 2014. Fisher exact test was used to compare the proportion of CMV viremia and CMV retinitis in patients transplanted between January 2010 and December 2013 with those transplanted in 2014. A total of 101 patients underwent allogeneic HSCT from January 2010 to December 2013; 32 (32%) tested positive for CMV viremia. No cases of CMV retinitis were identified. From January 2014 to December 2014, 28 patients underwent allogeneic HSCT; 13 patients (46%) had CMV viremia, not a statistically significant increase (P= .18). There were 5 cases of CMV retinitis diagnosed in those transplanted in 2014, a statistically significant increase compared with those transplanted in 2010-2013 (P= .0004). A multidisciplinary team was formed to review the literature and an ophthalmic screening protocol was developed. Our recent cluster of CMV retinitis in pediatric allogeneic HSCT patients may suggest a rise in incidence of CMV retinitis. We propose an ophthalmic screening protocol to diagnose retinitis in pediatric HSCT patients in the early, often asymptomatic stage.

Restrictive Palivizumab Use Does Not Lead to Increased Morbidity and Mortality in Pediatric Hematopoietic Stem Cell Transplantation Patients

Respiratory syncytial virus (RSV) is a common cause of infection in immunocompromised patients and can lead to significant morbidity and mortality in pediatric hematopoietic stem cell transplantation (HSCT) patients and patients with a primary immune deficiency (PID). Palivizumab is a humanized monoclonal antibody that targets the F glycoprotein on the surface of the RSV virus, preventing RSV replication. Palivizumab was initially licensed for the prevention of RSV infections in children at high risk of severe disease. Since licensure, the American Academy of Pediatrics (AAP) has issued guidelines to help ensure appropriate use of palivizumab in pediatric patients. In the 2014 edition of the guidelines, the AAP recognizes that severe and fatal disease secondary to RSV can be seen in patients receiving chemotherapy or patients who are immunocompromised because of other conditions. However, they recognize that no large clinical trials exist to support the use of palivizumab, and efficacy and safety data in this population are limited. Despite this, the AAP recommends considering prophylaxis for children younger than 24 months who are profoundly immunocompromised during the RSV season. Because of the high cost of palivizumab, the uncertainty of its efficacy as prophylaxis in hospitalized pediatric HSCT and PID patients, and secondary to recent data from our center that suggested immunocompromised patients diagnosed with RSV did not have worse outcomes, we implemented very restrictive criteria for the use of palivizumab in the 2015 to 2016 RSV season in our pediatric HSCT population. Despite these strict criteria, there was no change in the number of patients developing RSV during this season compared with previous seasons, and there was no change in RSV course in those patients developing RSV compared with previous seasons. Restricted use also resulted in a significant dose and cost savings. Based on our experience, we recommend only administering prophylaxis palivizumab to the youngest and most high-risk HSCT patients during the RSV season.

Sonographic Appearance of the Gallbladder in the Allogeneic Hematopoietic Stem Cell Transplant Population.

To determine whether gallbladder sonographic findings in hematopoietic stem cell (HSC) transplant patients can distinguish among hepatobiliary complications of HSC transplants (graft-versus-host disease [GVHD] and veno-occlusive disease) and biliary events (cholecystitis, cholangitis, and choledocholithiasis). All HSC transplant patients who underwent gallbladder sonography from 2009 through 2012 were identified. Complications and sonographic findings were recorded. Of 124 patients, 66 (53.2%) had an event: 33 (50.0%) had GVHD; 22 (33.3%) had veno-occlusive disease; 6 (9.0%) had a biliary event; 4 (6.0%) had veno-occlusive disease and GVHD; and 1 (1.5%) had veno-occlusive disease and a biliary event. Of all patients, 115 (92.7%) had 1 or more sonographic findings in the gallbladder, with sludge being most common in all groups. In patients with veno-occlusive disease, the second and third most common findings were pericholecystic fluid and wall thickening. In patients with GVHD, distension was the second most common. Patients with biliary events all had distension, and half had pericholecystic fluid. Patients with veno-occlusive disease were significantly more likely to have wall thickening than those with GVHD or no event (77.2% versus 36.3%; P= .005; and 77.2% versus 37.9%; P= .002) and more likely to have pericholecystic fluid than patients with GVHD (95.5% versus 45.5%; P = .0001), a biliary event (95.5% versus 50%; P = .02), or no event (95.5% versus 29.3%; P = .0001). The positive predictive value of any finding was low for all groups because findings were common in patients with no event. Sonographic abnormalities of the gallbladder after HSC transplants are common in patients with and without HSC transplant complications and in those with biliary events. No sonographic finding is useful to distinguish among complications in HSC transplant patients.

Validation of a Pediatric Early Warning Score in Hospitalized Pediatric Oncology and Hematopoietic Stem Cell Transplant Patients.

To evaluate the correlation of a Pediatric Early Warning Score with unplanned transfer to the PICU in hospitalized oncology and hematopoietic stem cell transplant patients. We performed a retrospective matched case-control study, comparing the highest documented Pediatric Early Warning Score within 24 hours prior to unplanned PICU transfers in hospitalized pediatric oncology and hematopoietic stem cell transplant patients between September 2011 and December 2013. Controls were patients who remained on the inpatient unit and were matched 2:1 using age, condition (oncology vs hematopoietic stem cell transplant), and length of hospital stay. Pediatric Early Warning Scores were documented by nursing staff at least every 4 hours as part of routine care. Need for transfer was determined by a PICU physician called to evaluate the patient. A large tertiary/quaternary free-standing academic children's hospital. One hundred ten hospitalized pediatric oncology patients (42 oncology, 68 hematopoietic stem cell transplant) requiring unplanned PICU transfer and 220 matched controls. None. Using the highest score in the 24 hours prior to transfer for cases and a matched time period for controls, the Pediatric Early Warning Score was highly correlated with the need for PICU transfer overall (area under the receiver operating characteristic = 0.96), and in the oncology and hematopoietic stem cell transplant groups individually (area under the receiver operating characteristic = 0.95 and 0.96, respectively). The difference in Pediatric Early Warning Score results between the cases and controls was noted as early as 24 hours prior to PICU admission. Seventeen patients died (15.4%). Patients with higher Pediatric Early Warning Scores prior to transfer had increased PICU mortality (p = 0.028) and length of stay (p = 0.004). We demonstrate that our institution's Pediatric Early Warning Score is highly correlated with the need for unplanned PICU transfer in hospitalized oncology and hematopoietic stem cell transplant patients. Furthermore, we found an association between higher scores and PICU mortality. This is the first validation of a Pediatric Early Warning Score specific to the pediatric oncology and hematopoietic stem cell transplant populations, and supports the use of Pediatric Early Warning Scores as a method of early identification of clinical deterioration in this high-risk population.

Community Acquired Respiratory Viral Infections (CARV) in Patients with Acute Leukemia and Hematopoietic Stem Cell Transplant (HSCT) Recipients

CARV infections are significant causes of morbidity and mortality in adult HSCT recipients. In 2008, the FDA approved the use of multiplex PCR assay to detect respiratory viruses. CARV infections have been studied mostly in the HSCT population where lymphopenia has been identified as a risk factor for poor outcomes. These infections have been less well studied in the acute leukemia population. This report, however, encompasses both patient populations.

Increasing Vaccination Compliance in the Pediatric Hematopoietic Stem Cell Transplant Population

Increasing Vaccination Compliance in the Pediatric Hematopoietic Stem Cell Transplant Population

Safe and Effective Prophylaxis with Bimonthly Intravenous Pentamidine in the Pediatric Hematopoietic Stem Cell Transplant Population.

Without prophylaxis, Pneumocystis jiroveci pneumonia (PCP) develops in 5%-15% of pediatric hematopoietic stem cell transplant (HCT) patients with mortality above 50%. Trimethoprim-sulfamethoxazole is a standard PCP prophylaxis; pentamidine is frequently used as second-line prophylaxis because of trimethoprim-sulfamethoxazole's potential for cytopenias. Monthly intravenous (IV) pentamidine has variable efficacy with PCP infection rates of 0%-10% in pediatric patients, and higher breakthrough rates in those younger than 2 years. We hypothesized that bimonthly (twice monthly) pentamidine might have equivalent safety and improved efficacy; therefore, we conducted a retrospective analysis of bimonthly pentamidine PCP prophylaxis. We retrospectively reviewed records of all pediatric HCT patients who received bimonthly IV pentamidine between December 2006 and June 2013, and collected data regarding demographics, clinical course, prophylaxis rationale, laboratory values and adverse events. Between December 2006 and June 2013, 111 pediatric HCT patients received bimonthly IV pentamidine (574 doses, 8758 patient-days); 31 patients were younger than 2 years at initiation. In the majority (53% of courses), pentamidine was initiated because of cytopenias. Fourteen patients (12.6% of patients, 2.4% of doses) experienced a side-effect prompting discontinuation, including 3 patients with infusion-related hypotension/anaphylaxis and 3 with acute pancreatic dysfunction. No patients [0% (95% confidence interval: 0-3.2)] developed PCP during or after bimonthly IV pentamidine prophylaxis. Bimonthly IV pentamidine for PCP prophylaxis in the HCT pediatric population has comparable safety to monthly IV pentamidine and was highly effective, including in the very young. Bimonthly IV pentamidine should be considered in pediatric patients as second-line PCP prophylaxis.

Incidence and predictors of respiratory viral infections by multiplex PCR in allogeneic hematopoietic cell transplant recipients 50 years and older including geriatric assessment

Community respiratory viruses (CRV) are important agents of morbidity and mortality within the allogeneic hematopoietic stem cell transplant (HCT) population. Few proven methods to prevent CRV infections exist. No studies have specifically investigated their impact on older patients. We reviewed patients 50 years and older undergoing HCT between 2009–2013 to determine the incidence of CRV infection using multiplex PCR and risk factors for infection including geriatric assessment (GA). Thirty-two first episode CRV infections occurred in 118 patients for a 1-year cumulative incidence of 27.2% (CI: 19.4–35.6%). Hospitalization and mortality were restricted to those who developed lower respiratory tract infections (LRTI) (n = 22, 69%). CRV infection contributed to 8 deaths (36% of LRTIs) and 7 of these patients were taking steroids for GvHD at the time of infection. Health impairments by GA did not translate into increased risk for CRV infection. Steroid use at time of LRTI was associated with high mortality.

A Model Estimating Indirect Costs of Premature Death Associated with Severe Hepatic Veno-Occlusive Disease (sVOD) Among Hematopoietic Stem Cell Transplant (HSCT) Patients in the United States (U.S.)

IntroductionHepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of HSCT and is characterized by hepatomegaly, right upper quadrant pain, jaundice, and ascites (Gratwohl A et al JAMA 2010). Severe VOD (sVOD) is clinically characterized by multi-organ dysfunction and is estimated to have a mortality rate of over 80% (Coppell JA et al BBMT 2010). VOD and particularly sVOD pose a significant economic burden in direct medical costs by adding an estimated $53,000 to HSCT (2004 U.S. dollars; Saito et al BBMT 2008), or $78,000 in 2015 dollars. However, little research has been conducted in ascertaining the indirect costs associated with premature death due to VOD. In our study, we developed an economic model to evaluate the indirect cost associated with premature death due to sVOD among HSCT patients in the U.S.MethodsAn Excel-based model was developed to estimate the indirect cost associated with premature death due to sVOD among HSCT patients. Model inputs included prevalence of sVOD as well as mortality, age, salary, employment rate, and life expectancy. Inputs were obtained from the published literature, Center for International Blood & Marrow Transplant Research (CIBMTR), Centers for Disease Control and Prevention (CDC), U.S. Census Bureau, and Organisation for Economic Co-operation and Development (OECD).The model considered lost productivity as the result of premature death by calculating the number of years between the age of sVOD-related death and the assumed age of retirement (65 years old); it was assumed that the lifetime salary reflected underlying productivity of HSCT survivors who did not develop sVOD. Annual salary and life expectancy among HSCT survivors were adjusted from the general population to reflect decreased productivity in the first 2 years immediately following HSCT. Annual average salary inputs by age categories were assumed to be the same as the general population. Age of the working population was assumed to be between 18 and 65 years old.Excess mortality from sVOD was calculated as number of deaths among sVOD patients minus the number of deaths among HSCT patients who did not develop sVOD. Indirect cost was expressed as the cumulative salary for all productive years contributed by a patient and included a 3% discount for each additional year. Total lost productivity years and indirect costs by age category were obtained by multiplying each respective per patient value by the number of excess deaths in each age category. A sensitivity analysis was performed to examine the impact of changes in key model parameters on model results.ResultsThe model estimated 361 excess deaths per year due to sVOD in the HSCT population. The excess deaths due to sVOD were associated with indirect costs of over $68 million due to reduced life expectancy and consequent productivity loss. AlloSCT patients were younger on average, resulting in greater indirect costs ($39 million) compared to AutoSCT ($29 million). AlloSCT patients lost 3,637 productive years on average compared to 2,353 lost productive years for AutoSCT patients despite fewer patients receiving AlloSCT than AutoSCT. A sensitivity analysis showed that the total indirect costs due to overall VOD (non-severe and severe) were as high as $73.3 million.ConclusionsVOD imposes a substantial economic burden on patients in terms of excess deaths, lost productivity, and indirect costs. The model underestimates indirect costs largely due to not accounting for productivity loss among children and their caregivers or those older than 65. It also does not calculate productivity loss among HSCT survivors. Future research is warranted to elicit the additional indirect costs associated with non-severe VOD. [Display omitted] [Display omitted] [Display omitted] DisclosuresQuock:Jazz Pharmaceuticals: Employment, Equity Ownership. Zhou:Jazz Pharmaceuticals: Other: Analysis Group received funding for this analysis from Jazz Pharmaceuticals, Inc.; Analysis Group: Employment. Dai:Jazz Pharmaceuticals: Other: Analysis Group received funding for this analysis from Jazz Pharmaceuticals, Inc.; Analysis Group: Employment. Tang:Jazz Pharmaceuticals: Other: Analysis Group received funding for this analysis from Jazz Pharmaceuticals, Inc.; Analysis Group: Employment. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

A pilot study comparing the neutropenic diet to a non-neutropenic diet in the allogeneic hematopoietic stem cell transplantation population.

Historically, dietary restrictions imposed on patients undergoing hematopoietic stem cell transplantation (HSCT) were severe and limited to prevent exposure to foodborne organisms. With improvements in supportive care and anti-infective agents, the necessity of the neutropenic diet for this population has been in question. This study aimed to determine whether the incidence of infection differs and to analyze the nutritional status in patients undergoing myeloablative allogeneic HSCT with a neutropenic diet as compared to those with a diet without restrictions. This study was a randomized, controlled prospective pilot study beginning within the first 24 hours of the start of the conditioning regimen. Patients were randomized to receive a neutropenic diet or a diet without restrictions. All patients received care in a high-efficiency particulate air-filtered room on the inpatient adult blood and marrow transplantation unit (ABMTU). All patients received antibacterial and antifungal prophylaxis. Patients were followed until the end of neutropenia (defined as absolute neutrophil count of greater than 500 for three days) or until discharge from the inpatient ABMTU. In 46 evaluable patients, no significant difference was found between infection rates or nutritional status. The neutropenic diet did not offer a protective effect against infection in patients undergoing myeloablative allogeneic HSCT. No differences were found in nutritional status between the two groups.

Acute Cholecystitis Is a Common Complication after Allogeneic Stem Cell Transplantation and Is Associated with the Use of Total Parenteral Nutrition

The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound.

Epidemiology and Outcomes of Respiratory Virus Infections in Adult Acute Leukemia and Hematopoietic Stem Cell Transplant Patients

BACKGROUNDRespiratory virus infections (RVI) are significant cause of morbidity and mortality in adult patients with hematopoietic stem cell transplant (HSCT) recipients, causing delay in administering chemotherapy and HSCT, increased hospital stay and in occasionally resulting in mortality. In 2008, the FDA approved the use of multiplex PCR assay to detect respiratory viruses. Our institution has been using the multiplex PCR technique for approximately four years. With this technology the time to diagnosis of a RVI became shorter and detection of multiple viruses at the same time became feasible.RVIs have been studied more exclusively in the HSCT population where lymphopenia has been identified for poor outcomes. These infections have been less well studied in the acute leukemia population. This report, however, encompasses both patient populations. The natural progression of RVIs apart from influenza is poorly understood. The viruses isolated from the upper respiratory tract, development of lower respiratory tract infection (LRI), as well as overall survival of the patients identified with RVIs are reported here.STUDY DESIGNThis is a retrospective cohort study of adult patients (>=18yrs) with acute leukemia and/or after HSCT diagnosed with laboratory documented RVI between May 1st 2010 and March 1st2014. A list of positive RVIs from multiplex PCR was retrieved from the hospital laboratory based on patients with specific ICD-9 codes.RESULTSBetween May 2010 to March 2014, there were 208 episodes of RVI in 122 patients. Out of these, 77 patients were post-HSCT and 45 patients had acute leukemia without undergoing HSCT. Out of these episodes, 85 were caused by rhinovirus, 37 by coronavirus, 18 by RSV, 35 by parainfluenza, 15 by influenza, 12 by metapneumovirus, 3 by adenovirus, 3 by poly-viral infection. 189 episodes were initially diagnosed as an upper respiratory tract infection (URI). There were 47 episodes of LRI; of these 32 (16.9%) had a prior URI with rhinovirus (n=13), coronavirus (n=5), parainfluenza (n=4), RSV (n=4), influenza (n=3) and poly-viral infections (n=2). 15 (7.2%) episodes were LRI at initial presentation (4 metapneumovirus, 4 parainfluenza, 2 RSV, 3 rhinovirus, 1 coronavirus, 1 adenovirus). Out of the 122 patients there were 7 deaths (5.7%).CONCLUSIONThe availability of multiplex PCR has allowed for the identification of respiratory viruses responsible for URI in this patient population. Most of these infections have limited clinical consequences. However, in our study 25% of the episodes either presented with or progressed to LRI. The exact role of respiratory virus in causing LRI is difficult to determine in a retrospective study. DisclosuresOff Label Use: Treating MDS with one of these regimens: (1) nelfinavir, (2) bortezomib, (3) metformin + simvastatin, (4) metformin + seliciclib, (5) nelfinavir + bortezomib, (6) nelfinavir + ruxolitinib, (7) nelfinavir + simvastatin, (8) nelfinavir + sorafenib, (9) nelfinavir + trametinib, (10) ponatinib + bortezomib, (11) nelfinavir + ponatinib, and (12) trametinib + simvastatin.